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Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death

ABSTRACT: The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. While not observed in mouse ILC2s, we have found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates FOXO1. Over time, the high surface density expression of CD155 in AML impairs expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profile has been validated by single-cell RNA sequencing. In both AML and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a new member of the cytolytic immune effector cell family.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247205 | GEO | 2024/01/01

REPOSITORIES: GEO

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Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death

Project description:The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. While not observed in mouse ILC2s, we have found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1CD112/CD155 interaction that inactivates FOXO1. Over time, the high surface density expression of CD155 in AML impairs expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profile has been validated by single-cell RNA sequencing. In both AML and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a new member of the cytolytic immune effector cell family.

2024-01-01 | GSE247207 | GEO

Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death

2024-01-01 | GSE247206 | GEO

Profiling of Granzyme B Secreting B cells

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Proteome of group 2 innate lymphoid cells (ILC2s) stimulated with IL33 and TL1A

Project description:We analyzed the total proteome of group 2 innate lymphoid cells (ILC2s) after different stimulation with interleukin-33 (IL-33), a cytokine playing a critical role in human asthma, and TL1A, a TNF-family cytokine also known to activate ILC2s. Upon combined stimulation with IL-33 plus TL1A, we show that lung ILC2s produce high amounts of IL-9 and acquire a transient ‘ILC9’ phenotype. This phenotype is characterized by simultaneous production of large amounts of type 2 cytokines (IL-5, IL-13 and IL-9), induction of the IL-2 receptor CD25 (Il2ra), and of the transcription factors IRF4, JunB and BATF, that form immune-specific complexes known to induce IL-9 expression.

2024-03-05 | PXD041987 | Pride

Transcriptional profiles of human circulating innate lymphoid cells and CD4 T helper cells

Project description:Innate lymphoid cells (ILCs) are part of the innate immune cell family. Three different subsets of ILCs, ILC1s, ILC2s and ILCPs can be identified in human peripheral blood. Based on their expression of transcription factors and cytokines, they are considered as being the innate counterparts of CD4 T helper subsets, namely Th1s, Th2s and Th17s. However, ILCs and Th cells have different roles in immunity. Therefore, we compared the transcriptomes of sorted ILC1s, ILC2s, ILCPs, Th1s, Th2s and Th17s from the peripheral blood of three different donors. RNA sequencing of ILC and Th subsets revealed differences in the expression of tens to hundreds of genes. These genes are involved in cell trafficking, innate activation and inhibitory functions. ILC and Th cell subsets also differ in their expressions of long-non coding RNAs.

2020-02-04 | E-MTAB-8494 | biostudies-arrayexpress

Specification of innate type-2 lymphocytes by the transcriptional determinant Gfi1

Project description:Innate type-2 lymphoid cells (ILC2s) function in immune responses against helminth parasites and are implicated in allergic inflammation and asthma. ILC2s are activated by the epithelial-derived cytokines IL-33 and IL-25 and are major sources of the type-2 cytokines IL-5 and IL-13. We show that the transcription factor Gfi1 promotes the generation of ILC2s and controls their responsiveness during Nippostrongylus brasiliensis infection as well as IL-33- or IL-25-instigated inflammation. Gfi1 directly activates Il1rl1, which encodes the IL-33 receptor. IL- 33 signaling upregulates Gfi1, thereby constituting a positive feedback loop that enables rapid and robust expansion of ILC2s in response to IL-33 signaling. Loss of Gfi1 in activated ILC2s results in an unusual effector state involving derepression of the IL-17 inflammatory program and co-expression of IL-13 with IL-17. ChIPseq reveals key Gfi1 targeted genes that are activated or repressed to maintain ILC2 identity. We propose that Gfi1 functions as a shared determinant within innate and adaptive immune cells to specify type-2 responses, while actively repressing the IL-17 effector state. ILC2s (~3 x 10^7 cells) were sorted from the MLN of IL-25-treated mice. Chromatin fragments bound by Gfi1 were subject to ChIP using Gfi1 antibodies and followed by high-throughput sequencing.

2013-09-13 | E-GEOD-50806 | biostudies-arrayexpress

Cytotoxic Granzyme C Expressing ILC1s Contribute to Antitumor Immunity and Neonatal Autoimmunity

Project description:Innate lymphocytes are integral components of the cellular immune system that coordinates host defense against a multitude of challenges and can trigger immunopathology when dysregulated. Natural killer (NK) cells and innate lymphoid cells (ILCs) are innate immune effectors postulated to functionally mirror conventional cytotoxic T lymphocytes and helper T cells, respectively. Here, we show that the cytolytic molecule granzyme C was surprisingly expressed in cells with the phenotype of type 1 ILCs (ILC1s) in mouse liver and salivary gland. Cell fate-mapping and transfer studies revealed that granzyme C-expressing innate lymphocytes could be derived from ILC progenitors and did not interconvert with NK cells, ILC2s, or ILC3s. Granzyme C defined a maturation state of ILC1s, which required the transcription factor T-bet and to a lesser extent Eomes specifically in the salivary gland for their maintenance. Furthermore, transforming growth factor-b (TGF-b) signaling promoted maintenance of granzyme C-expressing ILC1s in the salivary gland and in the tumor of a transgenic breast cancer model, and their depletion caused accelerated tumor growth. ILC1s gained granzyme C expression following interleukin-15 (IL-15) stimulation, which enabled perforin-mediated cytotoxicity. Strikingly, constitutive activation of the IL-15-regulated transcription factor Stat5 in granzyme C-fate-mapped ILC1s triggered lethal perforin-dependent autoimmunity in neonatal mice. Thus, granzyme C marks a cytotoxic effector state of ILC1s, broadening their function beyond ‘helper-like’ lymphocytes.

2022-02-18 | GSE196716 | GEO

Human CD127 negative ILC2s show immunological memory.

Project description:Group 2 Innate Lymphoid Cells (ILC2s) are key players in type 2 immunity and contribute to maintaining homeostasis and responding to inflammation. ILC2s are implicated in the development of type 2 inflammation-mediated chronic disorders like asthma. While memory ILC2s have been identified in mouse, it is unknown whether human ILC2s can acquire immunological memory. Here, we demonstrate the persistence of CD45RO, a marker previously linked to inflammatory ILC2s, in resting ILC2s that have undergone prior activation. A high proportion of these cells concurrently reduce the expression of the canonical ILC marker CD127 in a tissue specific manner. Through isolation and in vitro stimulation of CD127- CD45RO+ ILC2s, we observed an augmented ability to proliferate and produce cytokines. CD127- CD45RO+ ILC2s are found in both healthy and inflamed tissues and display a gene signature of cell activation. Our findings suggest that human ILC2s can acquire innate immune memory and warrants a revision of the current strategies to identify human ILC2s.

2024-05-20 | GSE267098 | GEO

The transcription factor GATA3 is critical for the development of all IL-7Ra-expressing innate lymphoid cells (ILCs) and maintenance of type 2 ILCs

Project description:Innate lymphoid cells (ILCs) play critical roles during innate immune responses to pathogens and lymphoid organ development. IL-7Ra+ ILC subsets, similar to T helper (Th) cell subsets, produce distinctive effector cytokines. The molecular control of IL-7Ra+ ILC development and maintenance has yet to be dissected. Here we report that GATA3 is indispensable for the development of all IL-7Ra+ ILC subsets and T cells. Gata3 conditional deficient mice have no lymph nodes and are susceptible to Citrobactor rodentium infection. Genome-wide gene analyses indicate that GATA3 regulates similar set of cytokines and receptors in ILC2s and Th2 cells and is critical for the maintenance of ILC2s. Thus, GATA3 plays parallel roles in establishing and regulating both adaptive and innate lymphocytes. To identify GATA3 regulated genes in type 2 innate lymphoid cells by tamoxifen-mediated acute deletion of Gata3 gene.

2014-03-13 | E-GEOD-47851 | biostudies-arrayexpress

Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior

Project description:The innate immune system plays essential roles in brain development, including the remodeling of neuronal synapses. Innate lymphocytes are the most recently discovered member of the innate immune arsenal, whose developmental expansion and activation make them potential mediators of brain-immune communication during synapse formation. Here we show that group 2 innate lymphoid cells (ILC2s) and their cytokine Interleukin-13 (IL-13) signal directly to inhibitory interneurons to increase inhibitory synapse density in the developing brain. ILC2s expanded and produced IL-13 in the developing brain meninges. Loss of ILC2s or IL-13 signaling to interneurons decreased inhibitory, but not excitatory, cortical synapses. Conversely, ILC2s and IL-13 were sufficient to increase inhibitory synapses. Loss of this signaling pathway led to selective impairments in social interaction. These data define a type 2 neuroimmune circuit in early life that shapes inhibitory synapse development and behavior.

2024-11-01 | GSE236229 | GEO

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